Substituted triazinone derivatives

ABSTRACT

Triazinone derivatives represented by formula (I) 
     
       
         
         
             
             
         
       
     
     wherein:
 
Z, R1, R2, R3, R4, and n are as defined in the disclosure. Also disclosed are methods of preparing the compounds of formula (I) and their use in therapeutics.

This application is a continuation of International Application No.PCT/IB2009/006463, filed Jun. 25, 2009, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofEuropean Patent Application No. 08290617.3 filed Jun. 26, 2008.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral tauopathies.

Interestingly, protein kinase B (AKT) phosphorylation of GSK3β resultsin a loss of its kinase activity, and it has been hypothesized that thisinhibition may mediate some of the effects of neurotrophic factors.Moreover, phosphorylation by GSK3β of β-catenin, a protein involved incell survival, results in its degradation by an ubiquitinilationdependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as p53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseasesand other pathologies where GSK3β is deregulated (Nature reviews Vol. 3,June 2004, p. 479-487; Trends in Pharmacological Sciences Vol. 25 No. 9,September 2004, p. 471-480; Journal of neurochemistry 2004, 89,1313-1317; Medicinal Research Reviews, Vol. 22, No. 4, 373-384, 2002).

The neurodegenerative diseases include, in a non-limiting manner,Parkinson's disease, tauopathies (e.g. Fronto temporal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy), Wilson's disease, Huntington's disease (The Journal ofbiological chemistry Vol. 277, No. 37, Issue of September 13, pp.33791-33798, 2002), Prion disease (Biochem. J. 372, p. 129-136, 2003)and other dementia including vascular dementia; acute stroke and othertraumatic injuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis (European Journal of Neuroscience, Vol. 22, pp. 301-309, 2005)peripheral neuropathies; retinopathies and glaucoma. Recent studies havealso shown that inhibition of GSK3β results in neuronal differentiationof embryonic stem cells (ESC) and support the renewal of human and mouseESCs and the maintenance of their pluripotency. This suggests thatinhibitors of GSK3β could have applications in regenerative medicine(Nature Medicine 10, p. 55-63, 2004).

Inhibitors of GSK3β may also find application in the treatment of othernervous system disorders, such as bipolar disorders (manic-depressiveillness). For example lithium has been used for more than 50 years as amood stabilizer and the primary treatment for bipolar disorder. Thetherapeutic actions of lithium are observed at doses (1-2 mM) where itis a direct inhibitor of GSK3β. Although the mechanism of action oflithium is unclear, inhibitors of GSK3β could be used to mimic the moodstabilizing effects of lithium. Alterations in Akt-GSK3β signaling havealso been implicated in the pathogenesis of schizophrenia.

In addition, inhibition of GSK3β could be useful in treating cancers,such as colorectal, prostate, breast, non-small cell lung carcinoma,thyroid cancer, T or B-cell leukaemia and several virus-induced tumours.For example, the active form of GSK3β has been shown to be elevated inthe tumors of colorectal cancer patients and inhibition of GSK3β incolorectal cancer cells activates p53-dependent apoptosis andantagonizes tumor growth. Inhibition of GSK3β also enhancesTRAIL-induced apoptosis in prostate cancer cell lines. GSK3β also playsa role in the dynamics of the mitotic spindle and inhibitors of GSK3βprevent chromosome movement and lead to a stabilization of microtubulesand a prometaphase-like arrest that is similar to that observed with lowdoses of Taxol. Other possible applications for GSK3β inhibitors includetherapy for non-insulin dependent diabetes (such as diabetes type II),obesity and alopecia.

Inhibitors of human GSK3β may also inhibit pfGSK3, an ortholog of thisenzyme found in Plasmodium falciparum, as a consequence they could beused for the treatment of malaria (Biochimica et Biophysica Acta 1697,181-196, 2004).

Recently, both human genetics and animal studies have pointed out therole of Wnt/LPR5 pathway as a major regulator of bone mass accrual.Inhibition of GSK3β leads to the consequent activation of canonical Wntsignaling. Because deficient Wnt signaling has been implicated indisorders of reduced bone mass, GSK3β inhibitors may also be used fortreating disorders of reduced bone mass, bone-related pathologies,osteoporosis.

According to recent data, GSK3β inhibitors might be used in thetreatment or prevention of Pemphigus vulgaris.

Recent studies show that GSK3beta inhibitor treatment improvesneutrophil and megakaryocyte recovery. Therefore, GSK3beta inhibitorswill be useful for the treatment of neutropenia induced by cancerchemotherapy.

Previous studies have shown that GSK3 activity decreases LTP, aelectrophysiological correlate of memory consolidation, suggesting thatinhibitor of this enzyme may have procognitive activity. Procognitiveeffects of the compound could find application for the treatment ofmemory deficits characteristic of Alzheimer's disease, Parkinsondisease, age-associated memory impairment, mild cognitive impairment,brain trauma, schizophrenia and other conditions in which such deficitsare observed.

Inhibitors of GSK3β may also find application in the treatment ofparenchymal renal diseases (Nelson P J, Kidney International Advanceonline publication 19 Dec. 2007) and in the prevention or treatment ofmuscle atrophy (J. Biol. Chem. (283) 2008, 358-366).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides as an object of the invention thetriazinone derivatives represented by formula (I) or salts thereof,solvates thereof or hydrates thereof:

wherein:Z represents a bond, a carbonyl group, a methylene group optionallysubstituted by one or two groups chosen from a C₁₋₆ alkyl group, ahydroxyl group, a C₁₋₆ alkoxy group;R1 represents a 4-pyridine ring;R2 represents a hydrogen atom, a C₁₋₆ alkyl;R3 represents a hydrogen atom, a C₁₋₆ alkyl group;R2 and R3 may form together a 6 membered cycle with the nitrogens caringR2 and R3 optionally substituted by 1 to 4 substituents selected from aC₁₋₆ alkyl group;R4 represents:

-   -   a phenyl ring, this ring being optionally substituted by 1 to 4        substituents selected from a C₁₋₆ alkyl group, a halogen atom, a        C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group,        a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂ perhalogenated        alkoxy group, a C₁₋₆ alkylsulfonyl group, a nitro, a cyano, an        amino, a C₁₋₆ monoalkylamino group or a C₂₋₁₂ dialkylamino        group, an acetoxy group, an aminosulfonyl group;        n represents 0 to 2; in form of a free base or of an addition        salt with an acid.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the triazinone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;malaria, bipolar disorders (manic depressive illness); schizophrenia;alopecia or cancers such as colorectal, prostate, breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukaemia,several virus-induced tumours and bone related pathologies; thetreatment of parenchymal renal diseases and in the prevention ortreatment of muscle atrophy; the treatment of cognitive and memorydeficit. The medicament could also find an application in regenerativemedicine.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the diseases are neurodegenerativediseases and are selected from the group consisting of Alzheimer'sdisease, Parkinson's disease, tauopathies (e.g. Fronto temporaldementia, corticobasal degeneration, Pick's disease, progressivesupranuclear palsy), Wilson's disease, Huntington's disease, Priondisease and other dementia including vascular dementia; acute stroke andothers traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis; peripheral neuropathies; retinopathies and glaucoma, and theaforementioned medicament in the form of pharmaceutical compositioncontaining the above substance as an active ingredient together with oneor more pharmaceutical additives.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the bones related pathologies areosteoporosis. The present invention further provides an inhibitor ofGSK3β activity comprising as an active ingredient a substance selectedfrom the group consisting of the triazinone derivatives of formula (I)and the salts thereof, and the solvates thereof and the hydratesthereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of triazinone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the triazinone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedor cyclo alkyl group having 1 to 6 carbon atoms, optionally substitutedby a straight, branched or cyclic C₁₋₆ alkyl group, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexylgroup, isohexyl group, cyclopropylmethyl group and the like.

The C₁₋₆ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen atoms have been substituted by a halogeno, for examplea CF₃ or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast, one hydrogen has not been substituted by a halogen atom;

The C₁₋₆ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group, isopentylamino groupand the like;

The C₂₋₁₂ dialkylamino group represents an amino group substituted bytwo C₁₋₆ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group and the like;

A leaving group L represents a group which could be easily cleaved andsubstituted; such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid; salts with organic acidssuch as acetic acid, propionic acid, tartaric acid, fumaric acid, maleicacid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acidand the like.

The acid-addition salts of the basic compounds are prepared by standardprocedures well known in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the triazinone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention.

The triazinone derivatives represented by the aforementioned formula (I)may have one or more asymmetric carbon atoms. As for the stereochemistryof such asymmetric carbon atoms, they may independently be either in (R)or (S) configuration, and the derivative may exist as stereoisomers suchas optical isomers, or diastereoisomers. Any stereoisomers in pure form,any mixtures of stereoisomers, racemates and the like fall within thescope of the present invention.

In a first embodiment of the invention, there is provided compoundswherein

Z represents a bond, a carbonyl group, a C₁₋₆ alkyl group optionallysubstituted by one or two groups chosen from a C₁₋₆ alkyl group, ahydroxyl group, a C₁₋₆ alkoxy group,R1 represents an 4-pyridine ring,R2 is a hydrogen, a C₁₋₆ alkyl group,R3 represents a hydrogen, a C₁₋₆ alkyl group;R2 and R3 may form together a 6 membered cycle, this cycle beingoptionally substituted by a C₁₋₆ alkyl group;R4 represents a phenyl, optionally substituted by 1 to 4 substituentsselected from an halogen, C₁₋₆ alkoxy group andn represents 0, 1, 2 in the form of a free base or of an addition saltwith an acid.

Examples of compounds of the present invention are shown in table 1hereinafter. However, the scope of the present invention is not limitedby these compounds. The nomenclature is given according to IUPAC rules.

A further object of the present invention includes the group ofcompounds of table 1 of formula as defined hereunder:

-   1.    (+/−)-6-(2-Hydroxy-2-phenyl-ethylamino)-1-methyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   2. 1-Methyl-6-phenethylamino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   3.    (+/−)-6-(2-Hydroxy-2-phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   4.    1-Methyl-6-(2-oxo-2-phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   5. 6-(2-Phenylethyl)amino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   6.    1-Methyl-6-(3-phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   7. 6-(3-Phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   8. 6-Phenylamino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   9. 6-Benzylamino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   10.    6-[2-(2-Methoxy-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   11.    6-[2-(3-Fluoro-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   12.    6-[2-(2,4-Dichloro-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   13.    6-[2-(3,4-Dimethoxy-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   14.    6-[2-(2-Fluoro-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   15.    6-[2-(3-Methoxy-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   16.    (+/−)-6-(1-Phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   17.    6-[2-(4-Fluoro-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   18.    6-[2-(2,5-Dimethoxy-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   19.    6-]Methyl-2-(phenylethyl)-amino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   20.    6-((S)-2-Phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   21.    6-((R)-2-Phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one-   22.    7,7-Dimethyl-9-(2-oxo-2-phenyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one-   23.    (−)-9-((S)-2-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one-   24.    9-[2-(2-Fluoro-phenyl)-ethyl]-7,7-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one-   25.    (+/−)-9-(2-Hydroxy-2-phenyl-propyl)-7,7-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one-   26.    7,7-Dimethyl-9-(3-phenyl-propyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one

As a further object, the present invention concerns also methods forpreparing the triazinone compounds represented by the aforementionedformula (I). These compounds can be prepared, for example, according tomethods explained below.

Preparation Method

Triazinone compounds represented by the aforementioned formula (I), maybe prepared according to the method described in the scheme 1.

(In the above scheme the definition of R1, R2, R3, R4, n and Z are thesame as those already described for compound of formula (I)).

Following this method, the triazinone derivative represented by theabove formula (III), wherein R is an alkyl group such as for examplemethyl or ethyl, R1, R2, are as defined for compounds of formula (I),are used as intermediates. Alternatively compounds of formula (III) areallowed to react with a compound of formula (II), wherein R4, R3, Z andn are as defined for compound of formula (I), at a suitable temperatureranging from 140° C. to 160° C. under ordinary air to obtain thecompound of the aforementioned formula (I).

Compound of formula (III) may be prepared according to the methoddefined in scheme 2, starting from compound of formula (IV). Theconditions which may be used are given in the chemical examples.

As a further object, the present invention concerns also intermediate(III) for preparing the triazinone compounds represented by theaforementioned formula (I). (In the above scheme the definitions of R,R1 and R2 are the same as already described.)

According to this method, the amidine of formula (IV), wherein R1 isdefined for compound of formula (I), is allowed to react with a compoundof formula (V). The reaction may be carried out in the presence of abase such as sodium hydroxide, in a mixture of solvent such astoluene/water, at a suitable temperature ranging from 25° to 140° C.under ordinary air to obtain an intermediate triazinone compound (IIIa).

The compound of formula (IIIa) is allowed to react with a compound offormula (VI), wherein L represents a leaving group, such a group may befor example a tosyl, a mesyl, a bromide and the like. The reaction maybe carried out in the presence of a base such as sodium methoxide, in analcoholic solvent such as methanol to afford the compound of formula(IIIb).

The compound of formula (IIIb), can react with a compound of formula(VII) to afford the compound of formula (III).

When R2 and R3 form a cycle, the triazinone compounds represented by theaforementioned formula (I), may also be prepared according to the methoddescribed in the scheme 3.

Compounds of formula (IV), (V), (VI), (VII), (VIII), (IX) and (XII) arecommercially available or may be synthesized according to well-knownmethods to one skilled in the art.

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, tauopathies(e.g. Fronto temporal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy), Wilson's disease, Huntington'sdisease, Prion disease and other dementia including vascular dementia;acute stroke and others traumatic injuries; cerebrovascular accidents(e.g. age related macular degeneration); brain and spinal cord trauma;amyotrophic lateral sclerosis, peripheral neuropathies; retinopathiesand glaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; malaria, manic depressiveillness; schizophrenia; alopecia; cancers such as colorectal, prostatebreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia, several virus-induced tumours and in bone relatedpathologies; parenchymal renal diseases or muscle atrophy. Themedicament could also find an application in regenerative medicine. Themedicament could also find an application in the treatment or preventionof Pemphigus vulgaris. The medicament could also find an application inthe treatment of neutropenia induced by cancer chemotherapy. Themedicament could also find an application for therapeutic treatment of adisease characterized by cognitive and memory deficits such as inAlzheimer's disease, Parkinson disease, age associated memoryimpairment, mild cognitive impairment, brain trauma, schizophrenia andother conditions in which such deficits are observed.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention; however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES Example 1 Compound No. 2 of Table 11-Methyl-6-[2-(phenylethyl)amino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one1.1 1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one

To a suspension of 4 g (18.16 mmol) of6-Methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one (synthesis asdescribed in U.S. Pat. No. 4,406,897) in 30 mL of anhydrousdimethylformamide was added 2.76 g (19.97 mmol) of potassium carbonate.The resulting mixture was allowed to stir at room temperature for 15min, cooled at 0° C. and 1.13 mL (18.16 mmol) of methyl iodide wereadded dropwise.

The mixture was warmed at room temperature and stirred for 2 h. Cooledwater was added and the mixture extracted with dichloromethane, driedover sodium sulfate and evaporated to dryness to afford 0.8 g (39%) ofthe pure product as a white powder.

MP: 216-218° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 8.80 (d, 2H), 8.20 (d, 2H), 3.50 (s, 3H), 2.80 (s, 3H).

1.21-Methyl-6-[2-(phenylethyl)amino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one

A mixture containing 0.1 g (0.43 mmol) of1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one and 54μl (0.43 mmol) of phenethylamine (commercially available) was stirred at140° C. for 2 h. 27 μl (0.215 mmol) of phenethylamine were added and themixture was stirred at 120° C. for 1 h. After cooling, the resultingmixture was triturated with methanol and diethyl ether. The resultingsolid was filtered, washed with diethyl ether to afford 0.06 g (46%) ofthe desired compound as a powder.

MP: 242-244° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 8.90 (d, 2H), 8.30 (brs, 1H), 8.10 (d, 1H), 7.60-7.20 (m, 5H),5.60 (brs, 1H), 4.90 (brt, 1H), 3.80 (dd, 1H), 3.60 (dd, 1H), 3.30 (s,3H).

Example 2 Compound No. 4 of Table 1Methyl-6-(2-oxo-2-phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one2.1 1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one

To a suspension of 4 g (18.16 mmol) of6-Methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one (synthesis asdescribed in U.S. Pat. No. 4,406,897) in 30 mL of anhydrousdimethylformamide was added 2.76 g (19.97 mmol) of potassium carbonate.The resulting mixture was allowed to stir at room temperature for 15min, cooled at 0° C. and 1.13 mL (18.16 mmol) of methyl iodide wereadded dropwise.

The mixture was warmed at room temperature and stirred for 2 h. Cooledwater was added and the mixture extracted with dichloromethane, driedover sodium sulfate and evaporated to dryness to afford 0.8 g (39%) ofthe pure product as a white powder.

MP: 216-218° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 8.80 (d, 2H), 8.20 (d, 2H), 3.50 (s, 3H), 2.80 (s, 3H).

2.21-Methyl-6-(2-oxo-2-phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one

To a suspension of 0.12 g (0.51 mmol) of1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one in 1 mLof 3-methyl-1-butanol was added 0.088 g (0.51 mmol) of2-Amino-1-phenyl-ethanone hydrochloride (commercially available). To theresulting mixture was added 7.1 mg (0.051 mmol) of potassium carbonate.The resulting mixture was stirred at 120° C. for 1 h. Then, 7.1 mg(0.051 mmol) of potassium carbonate were added each hour during 2 h.

After cooling, the resulting mixture was triturated with methanol anddiethyl ether.

The resulting solid was filtered, dissolved in methanol and purified onpreparatives thin layer chromatography eluting with a mixture ofdichloromethane/methanol/aqueous ammonia solution (29%) in theproportions 90/10/1 to afford 0.05 g (30%) of the desired compound.

Mp: 230-232° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 8.30 (brs, 1H), 8.60 (d, 2H), 8.10 (d, 2H), 7.90 (d, 2H), 7.70(d, 1H), 7.60 (d, 2H), 5.00 (d, 2H), 3.50 (s, 3H).

Example 3 Compound No. 9 of Table 16-Benzylamino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one

By analogy with the method described in example 1 (step 1.2), usingbenzylamine (commercially available) in place of phenethylamine and6-Methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one (synthesis asdescribed in U.S. Pat. No. 4,406,897) in place of1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one, toafford the product which was transformed into the hyrdochloride salt inthe usual manner to give 0.15 g (47%) of a white solid.

Mp: 198-200° C.

RMN ¹H (DMSO-d⁶; 200 MHz [+D₂O])

δ (ppm): 9.00 (d, 2H), 8.50 (d, 2H), 7.70 (d, 2H), 7.50 (t, 2H), 7.15(t, 1H).

Example 4 Compound No. 10 of Table 1 4.6-[2-(2-Methoxy-phenyl)ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one

By analogy with the method described in example 1 (step 1.2), using2-(2-Methoxy-phenyl)-ethylamine (commercially available) in place ofphenethylamine and6-Methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one (synthesis asdescribed in U.S. Pat. No. 4,406,897) in place of1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one, toafford the product which was transformed into the hyrdochloride salt inthe usual manner to give 0.11 g (51%) of a white solid.

Mp: 230-232° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 8.90 (brd, 2H), 8.30 (d, 1H), 8.00 (d, 1H), 7.30-7.10 (m, 2H),6.90-6.70 (m, 2H), 3.90 (s, 3H), 3.70 (t, 2H), 2.90 (t, 2H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin table 1. The compounds have been prepared according to the methods ofthe examples.

In the table, Me represents a methyl group, (Rot.) indicates thelevorotatory or dextrorotatory properties of the enantiomeric compound,(dec.) indicates the decomposition of the compound.

TABLE 1

Mp ° C. No. Rot R4 Z R1 R3 R2 n Alpha D salt  1 (+/−)

CHOH

H CH3 1 242-244 Free base  2

CH2

H CH3 1 215-217 Free base  3 (+/−)

CHOH

H H 1 245-247 Free base  4

CO

H CH3 1 230-232 Free base  5

CH2

H H 1 235-237 Free base  6

CH2

H CH3 2 173-175 Free base  7

CH2

H H 2 160-162 Hydrochloride (1:2)  8

bond

H H 0 188-190 Hydrochloride (1:2)  9

bond

H H 1 198-200 Hydrochloride (1:2) 10

CH2

H H 1 230-232 Hydrochloride (1:2) 11

CH₂

H H 1 197-199 Hydrochloride (1:2) 12

CH₂

H H 1 224-226 Hydrochloride (1:2) 13

CH₂

H H 1 172-174 Hydrochloride (1:2) 14

CH₂

H H 1 198-200 Hydrochloride (1:2) 15

CH₂

H H 1 190-192 Hydrochloride (1:2) 16 (+/−)

CHCH₃

H H 0 185-187 Hydrochloride (1:2) 17

CH₂

H H 1 179-181 Hydrochloride (1:2) 18

CH₂

H H 1 118-120 Hydrochloride (1:2) 19

CH₂

CH₃ H 1 175-177 Hydrochloride (1:2) 20 (S)

CH(CH₃)

H H 1 148-150 Alpha D: −32.9° (C = 0.79 g/100 ml DMSO) Hydrochloride(1:2) 21 (R)

CH(CH₃)

H H 1 151-153 Alpha D: +29.9° (C = 0.865 g/100 ml DMSO) Hydrochloride(1:2) 22

CO

1 148-150 Hydrochloride (1:1) 23 (−)

CH(OH)(S)

1 220-222 Alpha D: −34.7° (C = 0.7882 g/100 ml; MeOH) Free Base 24

CH₂

1 227-229 Hydrochloride (1:1) 25

COH(CH₃(Rac.)

1 248-250 Hydrochloride (1:1) 26

CH₂

1 223-225 Hydrochloride (1:1)

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Four different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm ³³P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta.

In a third protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01% Tween 20 buffer for onehour at room temperature in the presence of GSK3beta (total reactionvolume: 100 microliters).

In a fourth protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01% Tween 20 buffer for 90minutes at room temperature in the presence of commercial GSK3beta(Millipore) (total reaction volume: 100 microliters).

Inhibitors were solubilized in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:

NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH. (Woodgett, J. R. (1989)Analytical Biochemistry 180, 237-241.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 are between 0.1 nanomolar to 3 micromolarconcentrations.

For example, on the protocol 3, the compound No. 1 of table 1 shows anIC₅₀ of 0.372 μM and the compound No. 5 of table 1 shows an IC₅₀ of0.050 μM.

Formulation Example (1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1  30 mg Crystalline cellulose  60 mg Corn starch100 mg Lactose 200 mg Magnesium stearate  4 mg

(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20 mg

(3) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. A compound of formula (I):

wherein: Z represents a bond, a carbonyl group, or a methylene groupoptionally substituted by one or two groups chosen from a C₁₋₆ alkylgroup, a hydroxyl group, and a C₁₋₆ alkoxy group; R1 represents a4-pyridine ring; R2 represents a hydrogen atom or a C₁₋₆ alkyl; R3represents a hydrogen atom or a C₁₋₆ alkyl group; or R2 and R3 may formtogether a 6 membered cycle with the nitrogens caring R2 and R3optionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkylgroup; R4 represents: a phenyl ring, this ring being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂perhalogenated alkoxy group, a C₁₋₆ alkylsulfonyl group, a nitro, acyano, an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylaminogroup, an acetoxy group, or an aminosulfonyl group; and n represents 0to 2; or an acid addition salt thereof.
 2. A compound of formula (I):

wherein: Z represents a bond, a carbonyl group, a C₁₋₆ alkyl groupoptionally substituted by one or two groups chosen from a C₁₋₆ alkylgroup, a hydroxyl group, a C₁₋₆ alkoxy group; R1 represents a 4-pyridinering; R2 is a hydrogen or a C₁₋₆ alkyl group; R3 represents a hydrogenor a C₁₋₆ alkyl group; R2 and R3 may form together a 6 membered cycle,this cycle being optionally substituted by a C₁₋₆ alkyl group; R4represents a phenyl, optionally substituted by 1 to 4 substituentsselected from a halogen and a C₁₋₆ alkoxy group; and n represents 0, 1,or 2; or an acid addition salt thereof.
 3. The compound according toclaim 1 selected from the group consisting of:(+/−)-6-(2-Hydroxy-2-phenyl-ethylamino)-1-methyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;1-Methyl-6-(2-phenylethyl)amino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;(+/−)-6-(2-Hydroxy-2-phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;1-Methyl-6-(2-oxo-2-phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-Phenethylamino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;1-Methyl-6-(3-phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-(3-Phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-Phenylamino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-Benzylamino-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(2-Methoxy-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(3-Fluoro-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(2,4-Dichloro-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(3,4-Dimethoxy-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(2-Fluoro-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(3-Methoxy-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;(+/−)-6-(1-Phenyl-ethylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(4-Fluoro-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[2-(2,5-Dimethoxy-phenyl)-ethylamino]-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-[Methyl-(2-phenylethyl)-amino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-((S)-2-Phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;6-((R)-2-Phenyl-propylamino)-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one;7,7-Dimethyl-9-(2-oxo-2-phenyl-ethyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one;9-((S)-2-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one;9-[2-(2-Fluoro-phenyl)-ethyl]-7,7-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one;(+/−)-9-(2-Hydroxy-2-phenyl-propyl)-7,7-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one;and7,7-Dimethyl-9-(3-phenyl-propyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a][1,3,5]triazin-4-one;or an acid addition salt thereof.
 4. A compound represented by formula(X) wherein:

R1, R2 and R3 are as defined for the compound of formula (I) accordingto claim
 1. 5. A pharmaceutical composition comprising a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof and one or more pharmaceutical additives.
 6. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 2 ora pharmaceutically acceptable salt thereof and one or morepharmaceutical additives.
 7. A pharmaceutical composition comprising acompound according to claim 3 or a pharmaceutically acceptable saltthereof and one or more pharmaceutical additives.
 8. A method ofinhibiting the activity of glycogen synthase kinase 3-beta (GSK3-β),which comprises administering to a patient in need of said inhibition atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 9. A method oftreating or preventing a disease caused by abnormal glycogen synthasekinase 3-beta (GSK3-β) activity in a patient, comprising administeringto said patient a therapeutically effective amount of a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof.
 10. A method of treating or preventing a neurodegenerativedisease in a patient comprising administering to said patient atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 11. The methodaccording to claim 10, wherein the neurodegenerative disease is selectedfrom the group consisting of Alzheimer's disease, Parkinson's disease,tauopathies, vascular dementia, acute stroke, traumatic injuries,cerebrovascular accidents, brain cord trauma, spinal cord trauma,peripheral neuropathies, retinopathies and glaucoma.
 12. A method oftreating or preventing a disease in a patient, comprising administeringto said patient a therapeutically effective amount of a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof, wherein said disease is selected from the group consisting ofnon-insulin dependent diabetes; obesity; manic depressive illness;schizophrenia; alopecia; cancers; parenchymal renal diseases and muscleatrophy.
 13. The method according to claim 12 wherein cancer is selectedfrom the group consisting of breast cancer, non-small cell lungcarcinoma, thyroid cancer, T or B-cell leukemia and virus-inducedtumors.
 14. A method of treating or preventing malaria in a patient,comprising administering to said patient a therapeutically effectiveamount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 15. A method of treating orpreventing a bone disease in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of formula (I)according to claim 1 or a pharmaceutically acceptable salt thereof. 16.A method of treating or preventing Pemphigus vulgaris in a patient,comprising administering to said patient a therapeutically effectiveamount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 17. A method of treating orpreventing neutropenia induced by cancer chemotherapy in a patient,comprising administering to said patient a therapeutically effectiveamount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 18. A method of treating adisease characterized by cognitive and memory deficits in a patient,comprising administering to said patient a therapeutically effectiveamount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.